Jou et al. demonstrated that IL-25-activated group 2 innate lymphoid cells (ILC2) created an immune suppressive microenvironment and promoted mApc-driven intestinal tumorigenesis. Higher levels of IL-25 were associated with poor prognosis in human intestinal tumors, and genetic ablation of IL-25 reduced intratumoral ILC2s and MDSCs, decreased tumor growth, and improved survival of Apc1322T/+ spontaneous mouse model of CRC. ILC2-produced IL-4 and IL-13 promoted MDSC-mediated immune suppression. Therapeutic blockade of the IL-25–ILC2 axis reduced intratumoral ILC2s and MDSCs, enhanced antitumor immunity, and decreased tumor burden.
Contributed by Shishir Pant
ABSTRACT: Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection and are associated with inappropriate allergic reactions. IL-33-activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that intestinal IL-25-activated ILC2s created an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression had reduced survival and increased IL-25R-expressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired antitumor responses. Ablation of IL-25 signaling reduced tumors, virtually doubling life expectancy in an Apc mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promoted intratumoral ILC2s, which sustained tumor-infiltrating MDSCs to suppress antitumor immunity. Therapeutic antibody-mediated blockade of IL-25 signaling decreased intratumoral ILC2s, MDSCs, and adenoma/adenocarcinoma while increasing antitumor adaptive T cell and interferon-γ (IFN-γ)-mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33 as well as ILC2s in cancer cannot be generalized. The protumoral nature of the IL-25-ILC2 axis in CRC highlights this pathway as a potential therapeutic target against CRC.